In my last post?Part 2 of this diet and inflammation seriesI discussed the cells?called macrophages?which actually affect the inflammatory response, and how the amino acid glycine is crucial in regulating the activation of the macrophages at the level of the cell surface membrane. In the present installment, I’ll be discussing the propagation and amplification of the inflammatory response, and the key roles played by two other nutrients: salicylic acid and omega-3 (v. omega-6) fatty acids.
The cell membrane itself is made up mainly of molecules called phospholipids; natural soap-like molecules which each contain two fatty acids. Upon cellular activation, some of these phospholipid molecules are broken down such that one of the fatty acids is enzymatically converted to a messenger molecule?a prostaglandin?which diffuses away to activate?or inhibit the activation of?other cells it reaches (Such local messenger molecules are known as paracrine factors.) The enzyme that catalyzes the key step in the process is called a cyclooxygenase 2 (COX2). Salicylic acid inhibits the activity of COX2. (The synthetic drug aspirin, or acetylsalicylic acid, is a much more potent COX2 inhibitor; more on this later.)
The type of prostaglandin molecule released reflects the composition of the type of fatty acids that make up the membrane, which in turn reflects the fatty acid composition of the diet. The prostaglandins that amplify the inflammatory activation are made from the omega-6 fatty acid, arachidonic acid (AA); whereas prostaglandins that inhibit this activation are made from the omega-3 fatty acid, eicosapentaenoic acid (EPA).
Hence, the greater the preponderance of omega-6 fatty acids in the diet (largely from seed oils, e.g., corn, soybean, sunflower, peanut) as opposed to omega-3 (fish or krill oil, flaxseed oil), the greater the amplification of the pro-inflammatory prostaglandin signal. (The optimal dietary ratio of omega-6 to omega-3 is about 3 or 4 to one; although whether either type of these polyunsaturated fatty acid types?”PUFAs”?are even essential to the human diet is still debated. Oils that seem to have a perfect balance of fatty acid types include walnut and olive oils.) Since the mass campaign to replace saturated fats with PUFAs over the latter half of the 20th century was largely successful in saturating the Western diet (and that of its livestock) with omega-6 PUFAs, it has clearly contributed to the high prevalence of chronic inflammation.
Meanwhile, the extent of COX2 activity is largely controlled by the concentration of salicylic acid. For some reason, salicylic acid is often viewed as a “nutraceutical”, rather than an everyday nutrient. In fact, it is often not viewed as a nutrient at all, although aspirin is viewed as something middle-aged and older individual are encouraged to take daily to prevent thrombotic events such as heart attacks and strokes. Aspirin, however, is a potent synthetic drug. Although it acts like salicylic acid (as well as increasing the actual salicylic acid content of the blood), it has potentially dangerous side-effects, like excess bleeding. Meanwhile, salicylic acid itself is a widespread botanical compound, particularly high in berry fruits, grapes and kiwis, and also present in significant amounts in nuts like almonds and walnuts. (It is also a key component of EVOO that is removed when olive oil is refined.)
It is my belief that it is salicylic acid, rather than the much touted polyphenols in fruits and nuts which are key to “anti-inflammatory diets”, and which lower risk of cardiovascular disease, for example. These polyphenols (e.g., resveratrol, quercetin) are great anti-oxidants, but the value of anti-oxidants is largely to mitigate the effects of inflammation. I think it’s better to stop inappropriate inflammation from getting started. I also believe, for example, that the “French paradox”?why French people eat such a high-fat diet but suffer a low rate of heart disease?is not due to the polyphenols in the wine they drink daily, but from the high salicylic acid content of grapes, and therefore, wine.
So it’s pretty clear how the typical Western diet that is low in fruits and vegetables, and low in omega-3?but high in omega-6 fats?contributes to excess inflammation, by helping to amplify?and therefore exaggerate’the inflammatory response. But getting back to the initiation of inflammation in the first place, why should glycine levels be low in the first place, and allow inflammation to develop inappropriately? After all, glycine is a non-essential amino acid, so you really should not have to eat any of it, right? And if the diet is rich in high-protein foods (meat, fish, poultry, eggs, dairy), we are also eating plenty of it.
The answer turns out to be quite simple: Although we discovered a century ago that we need to eat whole grains to avoid devastating deficiency diseases like pellagra, we never thought that we also need to eat whole cows, pigs, chickens and fish! But it turns out that the key to a healthy omnivorous diet is to balance the content of essential amino acid methionine that predominates in muscle with the glycine that predominates in the bones and connective tissues, the parts we usually throw away.
The specifics of the biochemistry’the metabolic interactions of glycine and methionine and key intermediate metabolites and cofactors?are now understood, and present a fascinating picture of how our bodies’ metabolic machinery works as best it can with what we feed it to keep us alive and healthy. That will be the focus of my next post.
About the Author
Joel Brind, Ph.D. has been a Professor of Biology and Endocrinology at Baruch College of the City University of New York for 28 years and a medical research biochemist since 1981. Long specializing in steroid biosynthesis and metabolism and endocrine-related cancers, he has specialized in amino acid metabolism in recent years, particularly in relation to glycine and one-carbon metabolism. In 2010 he founded Natural Food Science, LLC to make and market glycine supplement products via http://sweetamine.com , which includes his own blog HERE.
I really like this series so far! The cellular mechanisms of inflammation are well explained and therefore easy to understand :)
Though, as a loyal 180D follower I’ve been limiting omega 6 for years now and I’ve supplemented with omega 3 in the past. Additionally I’ve been making sure I don’t over do on muscle meat and get plenty of glycine from other cuts of meat and great lakes gelatin for, I dunno, almost two years perhaps. And if that’s not enough, I even take 100mg of aspirin almost daily (for close to a year now I think) and eat/drink a lot of fruit/fruit juice (plenty of rasins, grapes and grape juice too)and get a fair amount of veggies in.
Still, I have a chronic sinus infection which I have had since somewhere in my childhood (don’t remember when it started, must have been really young because much later I started to realize that this pressure I had on my head constantly couldnt be normal). So… what gives? I got the glycine, the omego 3/6 ratio + a low quantity of PUFA, and the sylicic acid.
One thing I think was missing all along is magnesium. I’ve added it to my supplement list a couple of months ago and have been really been going all out with it. It has definately improved the speed at which I’m recovering. I attribute a lot of improvements in my health to it. One of those improvments is less pressure on my head from my sinusses.
*salicylic acid (I forgot to look up how it was actually spelled before pressing submit :9 )
I have noticed that dairy seems to trigger sinus problems with me.
I tried cutting dairy and other possible foods I might be allergic to so no quick fix there :P.
Oh, and and additional comment.
I’m pretty sure many 180D readers will disagree with this:
“we discovered a century ago that we need to eat whole grains”
Anthony Colpo wrote a nice article on this blog on whole grains and how they are detrimental to health.
Also I’m sure the nutrients in whole grains can be gotten from food less likely to cause harm.
Franz, are you taking any medications for something? I had exactly the same problem as you describe, pressure in the head and sinus. I found out it was because of steroids creams I used on my skin for eczema. As soon as I stopped applying those steroid creams, the pressure went away rather quickly, in a few weeks.
I’ve had this problem for atleast a decade and I almost never have used medication.
Sinus problems can probably be caused by a lot of things though I think the underlying reason often is excessive inflammation.
Just a weird suggestion like so many we never knew about:) Next time you go to the dentist ask them to measure your palate and make other measurements in your mouth. If you have a narrow jaw and your palate is high and narrow you might be suffering from it in the sinus area. Shot in the dark I know but mine is super narrow and high and the lack of support for the upper half of my face does cause some problems.
Haven’t gone to the dentist for years, not since I decided to only go to the dentist if I have a serious tooth ache :P.
Though indeed it might be worth considering if my anatomy might be causing my sinus problems. I do have a pretty broad jaw though.
Anthony Colpo writes about how horrible the phytic acid in whole grains is. But in his Cholesterol Cure book, he advocates taking supplemental phytic acid supplements to reduce iron stores.
I suppose he has a paranoid rant stored up for anyone who dares to point out this inconsistency to him…
Carl M, it may not be an inconsistency. I think he may advocate taking phytic acid apart from some or all foods so that they phytic acid does not bind to the good nutrients – he explained it in a series of letters back and forth with a woman that he posted on his blog.
I’m still not big on taking aspirin (don’t take it myself), because it not only increases bleeding time (by inhibiting platelet aggregation), but its chronic use also has a nasty habit of inducing “aspirin resistance”. So many people taking aspirin for its anti-coagulant activity are getting no benefit at all, and do not know it. They really should be getting their platelet function tested periodically to make sure they are not becoming aspirin-resistant.
As for my statement re: eating whole grains, my meaning was that to the extent that we eat grains, they need to be whole grains, in order to get the B-vitamins needed to metabolize the carbs. I was not suggesting that one should necessarily go “whole hog” on whole grains (Note that I like a diet of mixed metaphors:-)
As for sinus infections, I have been troubled by that at times, during the winter months. I assumed it was cold sensitivity, and glycine helps in that it keeps the fluids thin, as there is lots of fluid but no inflammation. Inflammation is what results in the really thick mucus that generates secondary infections. I had not given much thought to magnesium: Just as iron is what makes blood and red meat red; in exactly the same way, magnesium is what makes green plants green. (And this is a natural, chelated form of magnesium that I would not expect to be stripped out by phytic acid in nuts and grains.) Since my diet has plenty of greens, I always assumed magnesium intake was adequate. But I think I’ll have another look at what I eat: It may be that I don’t have enough greens during the winter months, magnesium supplements might be a good idea.
Hm, I’ve never heard anything about aspirin resistance. I’ll see what I can find about the topic.
The main reason I’m taking aspirin is because I tried it as an experiment and noticed I felt a little better (less stressed) with no side effects.
I also supplement with vitamin K2, which is needed for blood coagulation and I thought that could negate the effects of aspirin on bleeding time.
I think the reason magnesium is helping me is not because it directly effects inflammation but because I am deficient and restoring that balance is making my body function better.
I supplement because from what I’ve heard it is very difficult to get an ideal amount of magneisum through diet alone and the quickest way to restore balans is through supplementation.
I think Garrett Smith (he does the consultations for 180D) advices most people to supplement magnesium. He knows a lot about the topic and might be of interest to you if you wish to look into magnesium.
Vitamin K2 has an effect on coagulation in a completely different manner than what is inhibited by aspirin. Aspirin inhibits platelet aggregation, whereas vitamin K2 is essential for the synthesis of soluble clotting factors (enzymes made by the liver) II, VII, IX and X. But the main thing to keep in mind is that vitamin K2 is a natural nutrient (largely made for us by “good” bacteria in the gut), whereas aspirin is a synthetic drug (although 100 mg/day is a minimal dose).
Ah, I see, I wasn’t sure if vitamin K2 helped with it (I just read it somewhere)and I take it for other reasons than that. But thanks for clearing that up for me.
Come on Franz. You know exactly where you read that. This is R.Peat and D-Rods line on aspirin and K2 :).
It is accurate in the sense that diets consistent of mostly refined grains that weren’t fortified led to deficiency diseases like pellagra, which was discovered in the early days of vitamin B research. Modern grains are all fortified with B vitamins now, and if you eat other nutritious foods with your refined grains it doesn’t appear that eating whole grains vs. refined grains affords any noticeable health protection, which was more the point of Sir Colpo’s rant.
Would white willow bark be something that could be taken as a salicylic acid source that’s a safer alternative to aspirin?
“Salix” is the name of the willow tree genus, and salicylic acid its namesake, as willow bark is a rich source. But it is really such a widespread nutrient that a diet rich in fruits (including dried, juiced or fermented) and nuts will normally contain plenty of it. Willow bark extract certainly has been advocated as an aspirin substitute for such things as headaches. You would have to try it and see if it works.
Prof. Brind,
Thanks for this great series, which I just discovered today.
Thanks also, belatedly, for your response to my comment on another article where I described my consistently negative reaction (severe agitation and insomnia) to Mg glycinate.
I have yet to try either pure glycine or Sweetamine, but given that (1) the Mg glycinate was pure powder, and (2) I respond very positively to Mg in other forms, it is hard not to conclude that glycine is the issue.
Can you comment on Amy Yasko’s claim that glycine is a “fair-weather friend” in the brain: calming if GABA dominates, but excitotoxic if there is already a glutamate problem?
I’m already doing everything I can to increase GABA (PharmaGABA, theanine, taurine). And I have discovered that, for better or worse, drinking alcohol helps tremendously.
I know that glycine is stimulatory rather than inhibitory at the NMDA receptors. As Wikipedia says,
“Glycine is a required co-agonist along with glutamate for NMDA receptors. In contrast to the inhibitory role of glycine in the spinal cord, this behaviour is facilitated at the (NMDA) glutaminergic receptors which are excitatory.”
I’m not sure how to put this information to use, however.
I should stress that in other respects glycine seems strongly indicated. I eat a high-protein diet (difficult to get around as I seem to be producing very little insulin and cannot tolerate carbs), and I am clearly suffering from a wide range of inflammatory problems.
I am not all that knowledgeable about the complex interactions of the different amino acids and their derivatives in the brain. Yes, glycine is an excitatory co-activator for NMDA receptors and an inhibitory neurotranmitter via glycine receptors, but it is generally required in high concentrations in all tissues, as a sort of universal cell voltage regulator. As I noted in a comment on my previous post, it is difficult to imagine an excess of glycine, unless there is an abnormality in the glycine cleavage system (GCS), the main route of glycine clearance. Since the GCS is actually a multienzyme complex, and as several different abnormalities have been identified it is probably rare but not all that rare to have one bad copy of a gene for one of those enzymes, and that could be responsible for adverse idiosynchratic reactions to supplemental glycine. (That is speculative, of course, but that’s all I got:-)
I take mag glycinate but I try to use magnesium topically since it won’t affect my digestive system that way. As far as glycine itself I am leary of it. I’ve takem it off and on over the years, but while doing an ill advised Ray Peat dietary experiment I discovered I have a problem with histamines. That diet (as well as paleo) is full of histamine foods and histamine liberators. I was eating all kinds of gelatin all day long in the form of homemade jellos. I was a completely wired insomniac. with exhaustingly fast digestive transit times (think 10 times a day) I could only conclude that too much glycine was ramping up my excitatory neurotransmitters, ruining my digestion and keeping me up all night. During that period I also took 2-4 pure aspirin a day which I have since stopped.
The only thing that has worked since then is to take proteolytic and digestive enzymes and cycle those off and on with mega doses of food based Vitamin C which has produced a markedly stable digestion situation. Pain, swelling, healing, and sleep have all stabilized and moderately improved as long as I watch how much histamine I take in and how many DAO inhibitors I consume.
Sounds like you’ve arrived at a good solution for your physiology. BTW, Mg glycinate is 85% glycine, so I imagine your are getting what you need that way
This is interesting, Laura. Thank you!
No question, histamine is part of my problem. But I’ve found that Vitamin C makes my skin rashes worse. Some people say claim that this will only happen with unbuffered C, but I experience it with buffered C, too.
I tolerate camu camu much better, but it gets expensive.
May I ask specifically what form of food-based C is working for you? How much do you take?
@zanolachino As far as vitamin C goes I am working my way through a bag of powdered acerola Cherries. They supposedly have a high vitamin C content. I don’t know exactly how much C I take per day because the exact amount in this food is hard to figure, but I’m guessing somewhere around 5-10 grams a day. I’m pretty amazed at how good I feel taking this much. I try not to read too much into any of my experiments but I do less and less that is new these days, so if I try something I pretty much know it’s is the only change I’m making…
Whoa! 5-10 grams/day is a lot of Vitamin C! I checked a couple of brands of acerola powder available on the internet, and found between 180 and 384 mg per (1 teaspoon) serving. Even for the higher one, 5-10 grams would be between 15 and 30 teaspoons per day! Also, acerola contains lots of anti-oxidant bioflavonoids and salicylic acid. So even if the only change is the high intake of acerola powder, it’s hard to pinpoint the particular nutrient that makes the difference. A look at what else you eat every day might help clarify what is missing.
Is salicylic acid the same as salicylates? Many people can not tolerate fruits well. Some researchers say fructose in the fruits is toxin, others say salicylates causes problems. for people who can not tolerate fruits, especially fresh ones, how should we eat salicylic acid abundant fruits, fresh or cooked? does cooking destroy salicylic acid? How much volume do you suggest? thanks very much.
Essentially, yes: Salicylates, such as methyl salicylate (oil of wintergreen) are ester forms of salicylic acid, and break down to form salicylic acid in the body. (And in the ester form, like in oil of wintergreen-containing linaments, it goes in right through the skin).
And yes, too much salicylic acid can be toxic, and it may explain some fruit intolerances. Salicylic acid is very stable, to cooking, etc. However, its content in fruit varies with ripeness: It is much higher in unripe or barely ripe fruit. So anyone who is sensitive to too much salicylic acid would likely tolerate very ripe fruits (raw or cooked) better. Of course, anyone who is overly sensitive to any nutrient should keep their intake within moderate limits, and avoid sources which are particularly rich (like kiwis).
A lot of foods are extremely high in salicylates, especially dried fruits like raisins, dates, cherries, but also all of the berries are very high in sals.
And many vegetables have extremely high levels (tomatoes, zucchini, olives, radishes, peppers, sweet potatoes), as do almost all spices except for salt.
Just wanted to add that Ray Peat doesn’t believe there is such a thing as salicylate intolerance from foods. Not surprising, considering he swallows aspirin on a daily basis like after dinner mints.
I began taking your recommended 8g dosage of glycine about a month ago. I am now experiencing vertigo. Could this be a negative reaction to the glycine?
I never heard of anyone with that reaction, but idiosynchratic reactions are always possible. See if it goes away if you stop taking supplemental glycine, or back off on the amount you take. I suppose it could be related to some impurity in the glycine your are taking, although I haven’t heard of that either. If it doesn’t go away, I would certainly see a doctor about it: It might be entirely unrelated.
“French people eat such a high-fat diet but suffer a low rate of heart disease” – in all of this talk about PUFAs and Omega 3 and Omega 6 ratios, don’t the French eat a diet high in saturated fats? Do these contain Omega 3 and 6 or are they a totally separate category? If it is questionable that an optimum diet requires PUFA at all, does it require saturated fats? If so, at what proportion? Thanks.
Hi Joel,
Do you think glycine deficiency plays a role in the pathogenesis of lyme disease?
Ops, my previous comment was supposed to be on part 4. I’ll repost my question there.